CN1136855C - Cross-linked polymers for removing bile salts from patient - Google Patents

Abstract

A method for removing bile salts from a patient by ion exchange by administering to the patient a therapeutically effective amount of one or more highly crosslinked polymers characterized by a repeat unit having the formula or copolymer thereof, where n is an integer; R1 is H or a C1-C8 alkyl group; M is Z is O, NR3R, S, or (CH2)m; m=0-10; R3is H or a C1-C8 alkyl group; and R2 is where p=0-10, and each R4, R5, and R6, independently, is H, C1-C8 alkyl group, or an aryl group. The polymer is nontoxic and stable.

Description

Cross-linked polymers for the removal of bile salts from patients

Background Art of the Invention

The present invention relates to the removal of bile salts from a patient.

Sequestration and removal of bile salts (eg, cholate, glycocholate, glycochechilate, mesosulfocholate, and deoxycholate) from the patient can reduce the patient's cholesterol levels. Ion exchange resins that remove bile salts after administration through the digestive system have been used for this purpose. Removing bile salts will cause more bile salts to be produced in the body. Since the bioprecursor of bile salts is cholesterol, the metabolism of cholesterol to bile salts is accompanied by a decrease in cholesterol in the patient.

Technical scheme of the present invention

In a first aspect, the invention features a method of removing bile salts from a patient by ion exchange comprising administering to the patient a nontoxic and stable therapeutically effective amount of one or more highly crosslinked polymers. Polymers are characterized by repeating units of the formula or its copolymers.

或-Z-R²；Z是O，NR³，S，或(CH₂)_m；m＝0-10；R³是H或C₁-C₈烷基(可以是直链或支链、取代的或未取代的，例如甲基)；及R²是或

wherein n is an integer; R ¹ is H or C ₁ -C ₈ alkyl (which may be linear or branched, substituted or unsubstituted, such as methyl); M is

or -ZR ² ; Z is O, NR ³ , S, or (CH ₂ ) _m ; m=0-10; R ³ is H or C ₁ -C ₈ alkyl (can be linear or branched, substituted or unsubstituted, such as methyl); and ^R is or

Wherein P = 0-10, and each R ⁴ , R ⁵ and R ⁶ is independently H, C ₁ -C ₈ alkyl (which may be linear or branched, substituted or unsubstituted, such as methyl), or aryl (eg, having one or more rings and which may be substituted or unsubstituted, eg, phenyl, naphthyl, imidazolyl, or pyridyl).

"Nontoxic" means that the polymer or any ions released into the body are not harmful when a therapeutically effective amount is ingested. Preferably, such released ions into the body are actually beneficial to the patient. For example, the exchangeable ions are natural nutrients such as amino acids.

"Stable" means that the polymer does not dissolve when absorbed in therapeutically effective amounts, does not decompose to form deleterious by-products, and remains substantially intact for excretion of ion-exchanged ions from the body.

In a preferred embodiment, the polymer is completed by crosslinking a multifunctional crosslinking comonomer in an amount of about 1-25% (more preferably 2.5-20%) of the total weight of the unit.

The polymer also preferably comprises one or more hydrophobic comonomers such as N-alkyl and N-aryl derivatives of styrene, vinylnaphthalene, ethylvinylbenzene, acrylamide and methacrylamide, Alkyl and aryl acrylates, alkyl and aryl methacrylates, 4-vinyl biphenyl, 4-vinyl anisole, 4-aminostyrene, and fluorinated comonomers of any of these Derivatives (such as p-fluorostyrene, perfluorostyrene, hexafluoroisopropyl acrylate, hexafluorobutyl methacrylate, or heptadecylfluorodecyl methacrylate). Alkyl is preferably C ₁ -C ₁₅ alkyl, may be linear, branched or cyclic (eg cyclohexyl), and may be further substituted or unsubstituted. Aryl preferably has one or more rings and can be substituted or unsubstituted, eg phenyl, naphthyl, imidazolyl, or pyridyl. The polymer may also include one or more positively charged comonomers, such as vinylpyridine, dimethylaminomethylstyrene, or vinylimidazole.

A first preferred polymer example is characterized by repeating units of the formula or copolymers thereof

The polymer may also include as comonomers one or more of the following: n-butyl methacrylamide, hexafluorobutyl methacrylate, heptadecafluorodecyl methacrylate, styrene or its fluorinated Derivatives, 2-Vinylnaphthalene, 4-Vinylimidazole, Vinylpyridine, Trimethylammonium Ethylmethacrylate, Trimethylammonium Ethacrylate, 4-Vinylbiphenyl, 4-Vinylanisole, or 4-aminostyrene.

A second example of a preferred polymer is characterized by repeating units of the formula or copolymers thereof

The polymer may include as comonomers one or more of the following: isopropylacrylamide, styrene or its fluoride, hexafluoroisopropylacrylate, and trimethylammonium ethyl methacrylate.

A third example of a preferred polymer is characterized by repeating units of the formula or copolymers thereof

The polymer may also comprise styrene or its fluorinated derivatives as comonomer.

A fourth preferred example of the polymer is characterized by a repeating unit of the formula below or a copolymer thereof.

A fifth preferred example of the polymer is characterized by a repeating unit of the following formula or a copolymer thereof.

An example of a sixth preferred polymer is characterized by repeating units of the formula or copolymers thereof

The polymer may also comprise ethyl vinyl styrene as a comonomer.

A seventh preferred polymer example is characterized by a repeating unit of the formula or a copolymer thereof.

An eighth preferred polymer example is characterized by repeating units of the formula or copolymers thereof

The polymer may also comprise styrene or its fluorinated derivatives as comonomer.

In a second aspect, the invention features a method of removing bile salts from a patient by ion exchange comprising administering to the patient a therapeutically effective amount of one or more highly cross-linked polymers having repeating units of the formula or copolymer,

并且，每个R²、R³和R⁴各自为H，C₁-C₈烷基，或芳基，该聚合物服用后无毒并且稳定。Where n is an integer; R ¹ is H or C ₁ -C ₈ alkyl; L is -NH- or G is or

In addition, each of R ² , R ³ and R ⁴ is H, C ₁ -C ₈ alkyl, or aryl, and the polymer is nontoxic and stable after ingestion.

In a preferred embodiment, the polymer is crosslinked by a multifunctional crosslinking comonomer in an amount of about 1-25% (more preferably 2.5-20%) based on the total weight of the monomers. The polymer also preferably includes one or more of the aforementioned hydrophobic comonomers.

Examples of a first preferred polymer are characterized by repeating units of the formula or copolymers thereof The polymer may also comprise styrene or its fluorinated derivatives as comonomer.

Examples of a second preferred polymer are characterized by repeating units of the formula or copolymers thereof.

According to the first and second aspects of the invention, the polymer may be positively charged, or be capable of becoming charged at physiological pH after ingestion. For the latter, the charged ions are bound to negatively charged counterions that can be exchanged with bile salts after ingestion. If the polymer is positively charged, the polymer may be provided with one or more exchangeable counterions. Examples of suitable counterions include Cl ⁻ , Br ⁻ , CH ₃ OSO ₃ ⁻ , HSO ₄ ⁻ , HO ₄ ²⁻ , HCO ₃ ⁻ , CO ₃ ²⁻ , acetate, lactate, succinate, propionic acid Salt, butyrate, ascorbate, citrate, maleate, folate, amino acid derivatives, nucleotides, lipids, or phospholipids. The counter ions may be the same or different. For example, a polymer may contain two different types of counterions that are exchanged for the removal of bile salts. It is also possible to administer more than one polymer, each having a different combination of its intrinsic charge-balancing ions.

The present invention also includes therapeutic compositions for the removal of bile salts comprising a therapeutically effective amount of one or more of the polymers described above.

In another aspect, the present invention relates to a highly crosslinked polymer composition comprising a polymer having the following repeating unit

wherein R ¹ is H or methyl, Q is -NH-(CH ₂ ) ₃ - or -O-(CH ₂ ) ₂ , n is an integer, and at least one selected from vinylnaphthalene, vinylimidazole, styrene Fluorinated derivative, additional comonomer for fluorinated alkyl methacrylates.

In some preferred examples of this aspect, ^R1 is methyl and Q is -NH-( _CH2 ) _3- . The polymer may also include trimethylammonium ethacrylate or trimethylammonium ethylmethacrylate as comonomers. In another preferred embodiment, Q is -O-(CH ₂ ) ₂ .

Examples of suitable fluorinated styrene derivatives include p-fluorostyrene and pentafluorostyrene. Examples of suitable fluorinated alkyl methacrylates include hexafluorobutyl methacrylate and heptadecafluorodecyl methacrylate.

In another aspect of the present invention, it also relates to a highly crosslinked polymer composition comprising a polymer characterized by having the following repeating units,

wherein R ¹ is H or methyl, Q is -NH-(CH ₂ ) ₃ - or -O-(CH ₂ ) ₂ , n is an integer, and (a) styrene (b) B as an additional comonomer trimethylammonium acrylate or trimethylammonium ethylmethacrylate, wherein R ¹ is methyl and Q is -NH-(CH ₂ ) ₃ -.

In yet another aspect, the present invention relates to a method for synthesizing highly crosslinked polymers having hydrophobic and hydrophilic units, the method comprising reacting a hydrophilic monomer or a hydrophobic monomer in the presence of an alcoholic solvent.

In yet another aspect, the invention relates to a method of removing bile salts from a patient, the method comprising administering to the patient a therapeutically effective amount of a reaction product of:

(a) one or more highly crosslinked polymers having repeating units of the formula:

and salts and copolymers thereof, wherein n and m are integers, and each R ¹ , R ² and R ³ is independently H, or C ₁ -C ₈ alkyl; and

(b) at least one alkylating agent. The reaction product is nontoxic and stable after ingestion.

"Salt" means the protonation of the amine nitrogen in the repeat unit resulting in a positively charged nitrogen atom associated with its negatively charged counterion.

"Alkylating agent" means, when reacted with a crosslinked polymer, an alkyl group or derivative thereof (e.g., aralkyl, hydroxyalkyl, alkyl ammonium salts, alkylamides, or combinations thereof).

In preferred embodiments, this reaction product is crosslinked by a multifunctional crosslinking comonomer, wherein the comonomer is about 1-25% (more preferably 2.5-20%) of the total weight of the monomers.

或其盐或其共聚物。A first preferred polymer is characterized by repeating units of the formula:

or its salt or its copolymer.

A second preferred polymer is characterized by repeating units of the formula: or its salt or its copolymer.

Preferred alkylating agents have the formula RX, wherein R is C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ hydroxyalkyl, C ₁ -C ₂₀ aralkyl, C ₁ -C ₂₀ alkyl ammonium, or C ₁ -C ₂₀ alkylamido, X includes one or more electrophilic leaving groups. "Electrophilic leaving group" means a group that can be displaced by a nitrogen atom in a crosslinked polymer during alkylation. Examples of preferred leaving groups include halide, epoxide, tosylate, mesylate groups. For example, for an epoxy group, an alkylation reaction will cause the three-membered epoxy ring to open.

Examples of preferred alkylating agents include C ₁ -C ₂₀ alkyl halides (e.g. n-butyl halide, n-hexyl halide, n-octyl halide, n-decyl halide, n-dodecyl halide, n-dodecyl halide, n- -tetradecyl halide, n-octadecyl halide, and combinations thereof); C ₁ -C ₂₀ alkyl halides (e.g. 1,10-dihalodecane; C ₁ -C ₂₀ hydroxyalkyl halides (e.g. 11-halo-1-undecanol); C ₁ -C ₂₀ aralkyl halides (e.g. benzyl halides); C ₁ -C ₂₀ alkyl halide ammonium salts (e.g. (4-halobutyl) trimethyl Ammonium salt, (6-halohexyl)trimethylammonium salt, (8-halogenoctyl)trimethylammonium salt, (10-halogenodecanyl)trimethylammonium salt, (12-halogeno-dodecyl)trimethylammonium salt ammonium salts and combinations thereof); C ₁ -C ₂₀ alkyl epoxy ammonium salts (eg (glycidyl propyl) trimethyl ammonium salt); and C ₁ -C ₂₀ epoxy alkyl amides (eg N-( 2,3-propylene oxide) butanamide, N-(2,3-propylene oxide) hexanamide, and combinations thereof).

It is especially preferred to react the polymer with at least two alkylating agents. In a preferred embodiment, one of the alkylating agents is of the formula RX, wherein R is C ₁ -C ₂₀ alkyl, X includes one or more hydrophilic leaving groups (e.g., alkyl halides), and the other The alkylating agent is of the formula R'X, wherein R' is a _C1 - _C20 alkylammonium group and X includes one or more hydrophilic leaving groups (eg, alkylammonium halide salts).

In another preferred embodiment, one of the alkylating agents is RX, wherein R is C ₁ -C ₂₀ alkyl, X includes one or more hydrophilic leaving groups (e.g., alkyl halides), and the other The alkylating agent is R'X, wherein R' is _C1 - _C20 hydroxyalkyl, and X includes one or more hydrophilic leaving groups (eg, hydroxyalkyl halides).

In yet another preferred embodiment, one of the alkylating agents is a C ₁ -C ₂₀ dihaloalkane, and the other alkylating agent is a C ₁ -C ₂₀ alkylammonium salt.

The present invention provides an effective therapeutic method for removing bile salts from a patient (thus lowering the patient's cholesterol level). Such compositions are nontoxic and stable when administered in therapeutically effective amounts.

The present invention also provides efficient synthesis of polymers with both hydrophilic and hydrophobic units, ie the reaction is carried out in the presence of alcoholic solvents which are generally not considered good polymerization solvents due to their chain transfer properties.

Other features and advantages will be apparent from the following preferred embodiments and claims.

BEST EXAMPLE COMPOSITIONS OF THE INVENTION

Preferred polymers have the formula given in the Summary of the Invention section above. The polymer is highly crosslinked. The high level of crosslinking renders the polymer completely insoluble and limits the activity of the alkylation reaction product only in the gastrointestinal tract. Therefore, the composition is not systemically active, which will reduce side effects on the patient.

The polymer is preferably crosslinked by adding a crosslinking comonomer to the reaction mixture during the polymerization. Examples of suitable crosslinking comonomers include diacrylates and dimethacrylates (e.g. ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, dimethyl propylene glycol acrylate, butylene glycol dimethacrylate, polyethylene glycol dimethacrylate, polyethylene glycol diacrylate), methylene bisacrylamide, methylene bismethacrylamide, ethylene bis Acrylamide, ethylene bismethacrylamide, ethylene (H ₃ CH ₂ ) bismethacrylamide, ethylene bisacrylamide, divinylbenzene, bisphenol A dimethacrylate, and bisphenol A Diacrylate. These crosslinking comonomers are either commercially available or available in Mandeville et al. "Process for Adjusting Ion Concentration in a Patient and Compositions Therefor," USSN 08/065,113, filed May 20, 1993 (assigned to the same assignee of this patent application, Cited here as a reference) method for preparation. Typically, the amount of crosslinker is 1.0-25%, preferably 2.5-20%, based on the total weight of crosslinker and monomer.

Preferably, the polymer includes one or more comonomers that increase the overall hydrophobicity of the polymer. Since bile salts are hydrophobic, hydrophobic monomers can maximize the selectivity of the interaction between the polymer and bile salts.

Examples of suitable hydrophobic comonomers include, for example, acrylamide, methacrylamide, and N-alkyl groups thereof (e.g., methyl, ethyl, isopropyl, butyl, hexyl, dodecyl, cyclohexyl , dicyclohexyl) and N-aryl (e.g. phenyl, diphenyl) derivatives; alkyl and aryl acrylates and methacrylates (e.g. ethyl, propyl, butyl, dodecyl) , and its fluorinated derivatives (such as hexafluoroisopropyl acrylate, hexafluorobutyl methacrylate, heptadecafluorodecyl acrylate); styrene and its derivatives (such as dimethylaminomethylstyrene, 4 Aminostyrene, and its fluorinated derivatives, such as p-fluorostyrene, pentafluorostyrene); ethylvinylbenzene; vinylnaphthalene; vinylpyridine; vinylimidazole; 4-vinylbiphenyl, 4 , 4-Vinylanisole; and combinations thereof. The amount of hydrophobic comonomer used in the preparation of these polymers is from 1 to 75% by weight, preferably from 3 to 65%.

The desired level of hydrophobicity can also be conveniently obtained by appropriate choice of crosslinking comonomers. For example divinylbenzene is a suitable crosslinking comonomer and is also hydrophobic. Additionally, the major "impurity" in divinylbenzene is ethylvinylbenzene, a hydrophobic polymerizable comonomer that also contributes to the overall hydrophobicity of the polymer. Other hydrophobic crosslinking comonomers include bisphenol A diacrylate and bisphenol A dimethacrylate.

Crosslinked polymers can be reacted with one or more alkylating agents. Examples of preferred alkylating agents are given in the Summary of the Invention. A. Preparation of polymer Example 1. Preparation of poly(methacrylamidopropyltrimethylammonium chloride) (polyMAPTAC)

Into a 1000 mL 3-neck round bottom flask was added the following: methacrylamidopropyltrimethylammonium chloride (MAPTAC) (40 mL, 50% aqueous solution, 21 g), ethylene glycol dimethacrylate cross-linked copolymer Monomer (5.00 g, 4.76 mL), ethyl acetate (200 mL), 2-propanol (200 mL). The resulting solution was clear. The polymerization initiator AIBN (0.1 g) was then added and the reaction mixture was heated to 65°C. When the temperature reached 65°C, the solution was degassed with nitrogen for 5 minutes, at which point the solution became mixed, indicating that polymerization was in progress. The reaction was maintained at 65°C for an additional 3 hours, then cooled to room temperature.

The resulting polymer (hard and sticky) was combined with 500 mL of water to soften the polymer, which was then transferred to a mixer and blended with 1500 mL of 2-propanol and centrifuged. The mixture was decanted and transferred to another mixer with 100 mL of water. 800 mL of 2-propanol was added and the mixture was blended, settled and then decanted. The mixture was combined with 1000 mL of 2-propanol, blended, filtered and dried under vacuum to yield 12.6 g of polymer.

PolyMAPTAC crosslinked with 0.5% methylenebismethacrylamide crosslinking comonomer, polyMAPTAC crosslinked with 10% methylenebismethacrylamide crosslinking comonomer; and 10% Divinylbenzene cross-linked comonomer cross-linked poly-MAPTAC. Embodiment 2. Preparation of poly(vinylamine)

The first step is the preparation of ethylene bis-acetamide. Acetamide (118 g), acetaldehyde (44.06 g), copper acetate (0.2 g), and water (300 mL) were charged in a 1 L three-necked flask equipped with a condenser, thermometer, and mechanical stirring. Concentrated HCl (34 mL) was added and the mixture was heated to 45-50 °C and stirred for 24 hours. The water was removed in vacuo to give a thick sludge which crystallized on cooling to 5°C. Acetone (200 mL) was added and stirred for several minutes, the solid was filtered and discarded. The propanol was cooled to 0 °C and the solid was filtered off. The solid was rinsed with 500 mL of acetone and air dried for 18 hours to yield 31.5 g of ethylenebisacetamide.

The second step is to prepare vinylacetamide from ethylenebisacetamide, ethylenebisacetamide (31.05g), calcium carbonate (2g) and diatomaceous earth 541 (2g) are loaded with thermometer, mechanical Stir and top the 500 mL three-necked flask with the distillation head of the Vigreux column. The mixture was vacuum distilled at 35 mmHg by heating the flask to 180-225°C. A single fraction (10.8 g) was collected which contained most of the acetamide (determined by NMR) in addition to the product. The solid product was dissolved in isopropanol (30 mL) to form a crude vinylacetamide solution for polymerization.

Crude vinylacetamide solution (15 mL), divinylbenzene (1 g, technical grade, 55% purity, mixed isomers), and AIBN (0.3 g) were combined and heated to reflux for 90 minutes under nitrogen to form Solids precipitated. The solution was cooled, isopropanol (50 mL) was added, and the solid was collected by centrifugation. The solid was washed twice with isopropanol, once with water, and dried in a vacuum oven to yield 0.8 g of poly(vinylacetamide), which was used to prepare the following poly(vinylamine).

Poly(vinylacetamide) (0.79 g) was charged to a 100 mL single neck flask containing water (25 mL) and concentrated HCl (25 mL). The mixture was refluxed for 5 days and the solid was filtered off, rinsed once with water, twice with isopropanol and dried in a vacuum oven to give 0.77 g of product. Infrared spectroscopy analysis showed that there was still a large amount of amides (1656cm ^-1 ), but not much amines (1606cm ^-1 ). The reactant (ca. 0.84 g) was suspended in NaOH (46 g) and water (46 g) and heated to boiling point (ca. 140° C.). Since the foaming temperature is lowered, it is maintained at about 100°C for 2 hours. Water (100 mL) was added and the solid was collected by filtration. After rinsing the solid once with water, it was suspended in water (500 mL) and the pH was adjusted to 5 with acetic acid. The solid was then filtered off, rinsed with water, isopropanol, and dried in a vacuum oven to yield 0.51 g of product. Infrared spectroscopic analysis showed that a large number of amines had been synthesized. Embodiment 3. Preparation of poly(3-dimethylaminopropylacrylamide) (DMAPA)

In a 100 mL three-neck flask, dimethylaminopropylacrylamide (10 g) and methylenebisacrylamide crosslinking comonomer (1.1 g) were dissolved in 50 mL of water. The solution was stirred under nitrogen for 10 minutes. Potassium persulfate (0.3 g) and sodium metabisulfite (0.3 g) were each dissolved in 2-3 mL of water and mixed. After a few seconds, the above solution was added to the monomer solution, still under nitrogen. At this point a gel formed immediately and was left overnight. The gum was removed and mixed with 500 mL of isopropanol. The solid was filtered off and rinsed three times with acetone. A white solid powder was filtered off and dried in a vacuum oven to yield 6.1 g. Embodiment 4. Preparation of poly(dimethylaminopropylacrylamide hydrochloride) (DMAPA·HCl)

Dimethylaminopropylacrylamide (20.10 g) was dissolved in water (100 mL) and neutralized to pH 6.95 with concentrated HCl. Methylenebisacrylamide crosslinking comonomer (2.2 g) and water (100 mL) were added and warmed (34°) to dissolve. Potassium persulfate (0.2 g) and potassium metabisulfite (0.2 g) were added with stirring. After gelation, the solution was left for 6 hours, mixed 3 times with isopropanol (600 mL), and dried in a vacuum oven to obtain 14.47 g of the title polymer.

PolyDMAPA·HCl crosslinked with 10% methylenebismethacrylamide crosslinking comonomer was prepared in a similar manner. Example 5. Poly(dimethylaminopropylmethacrylamide hydrochloride) (DMAPMA.HCl)

Preparation of

Dimethylaminopropylmethacrylamine (20.0 g) was dissolved in water (100 mL) and neutralized to pH 6.94 with concentrated HCl. Methylenebisacrylamide crosslinking comonomer (2.2 g) was added and the solution was warmed (39°C) to dissolve. Potassium persulfate (0.3 g) and potassium metasulfite (0.3 g) were added with stirring under a nitrogen atmosphere. After gelation, the solution was left overnight, mixed twice with isopropanol (500 mL), and dried in a vacuum oven to yield 27.65 g of product. Some of the solid (3.2 g; sieved through a -80/+200 mesh sieve) was stirred in water (100 mL) for 50 minutes. Additional water (100 mL) was added and the solution was stirred for 36 minutes. The solid was collected by centrifugation, resuspended in water (400 mL), stirred for 15 minutes, and collected by centrifugation again. Finally the solid was suspended in water (500 mL), stirred for 90 minutes and collected by filtration. The solid was dried in a vacuum oven to give 0.28 g of the title polymer. Example 6. Poly(methacrylamidopropyltrimethylammonium chloride)copoly(n-butylmethylpropane

Preparation of enamide) (MAPTAC copolymerization-BuMA)

The comonomer n-butylmethacrylamide (BuMA) was prepared as follows:

In a 1 L flask, methacryloyl chloride (48.4 mL, 52.3 g, 0.500 mol) was dissolved in tetrahydrofuran (300 mL) and placed in an ice bath. A solution containing butylamine (36.6 g) and triethylamine (55.6 g) was added dropwise while maintaining the temperature at 5-15°C. After the solution was stirred for 5 minutes, the solid triethylamine hydrochloride was filtered off and discarded. The solvent was removed from the mother liquor in vacuo and the resulting yellow oil was used in the next preparation without further purification. Yield 71.58 g BuMA comonomer.

Into a 1000 mL three-neck round bottom flask was added the following: methacrylamidopropyltrimethylammonium chloride (MAPTAC) (108 mL, 50% aqueous solution, 56.8 g), ethylene glycol dimethacrylate cross-linked copolymer Monomer (19.62 g), BuMA comonomer (12.12 g) and 2-propanol (850 mL). The resulting solution was clear. The reaction mixture was then heated to 40°C while degassing with nitrogen. When the solution reached 40°C, the catalyst, 25 mL of an aqueous solution of potassium persulfate (0.75 g) and potassium metabisulfate (0.75 g), was added. At this point the solution immediately began to turn cloudy, indicating that polymerization was in progress. The reaction was maintained at 40°C for 24 hours, then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol and dried in vacuo to yield 64.54 g of the title polymer.

The polymer used in the test was washed twice with 800 mL each of water, followed by two washes each with 500 mL of methanol to obtain 34.5 g of purified polymer.

Crosslinked MAPTAC co-BuMA copolymers were also prepared using propylene glycol dimethacrylate as the crosslinking comonomer instead of ethylene glycol dimethacrylate as follows:

To a 1000 mL three-neck round bottom flask was added the following: methacrylamidopropyltrimethylammonium chloride (MAPTAC) (60 mL, 50% in water, 31.5 g), propylene glycol dimethacrylate crosslinking comonomer (9.81 g), BuMA comonomer (6.06 g), and 2-propanol (300 mL). The resulting solution was clear. The reaction mixture was then heated to 70°C while degassing with nitrogen. When the solution was heated to 70°C, catalyst AIBN (0.50 g) was added. At this point the solution immediately began to turn cloudy, indicating that polymerization was in progress. The reaction was maintained at 70°C for 6 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol and dried under vacuum to yield 23.3 g of polymer.

MAPTAC copolymerized BuMA (5%) cross-linked with 24% ethylene glycol dimethacrylate cross-linking comonomer was prepared in a similar manner and by adjusting the ratio of starting monomers, and 0.5% methylenebismethacrylamide Crosslinked comonomer crosslinked MAPTAC copolymerized BuMA (2%) and MAPTAC copolymerized BuMA crosslinked with 22% propylene glycol dimethacrylate crosslinked comonomer (14%). Example 7. Poly(methacrylamidopropyltrimethylammonium chloride)copoly(styrene)

Preparation of (MAPTAC Copolystyrene)

To a 1000 mL three necked round bottom flask was added the following, methacrylamidopropyltrimethylammonium chloride (MAPTAC) (60 mL, 50% in water, 31.5 g), divinylbenzene crosslinking comonomer (2.00 g), styrene comonomer (1.75 g), and 2-propanol (300 mL). The resulting solution was clear. The reaction mixture was then heated to 60°C and degassed with nitrogen. When the solution temperature reached 60°C, catalyst AIBN (0.50 g) was added. At this point the solution immediately began to turn cloudy, indicating that polymerization was in progress. The reaction was maintained at 60°C for 24 hours, then cooled to room temperature. After 7 hours, the mixture became very viscous and 100 mL of isopropanol was added for better stirring.

The resulting polymer was filtered and washed on the funnel with isopropanol and dried in vacuo to give 30.9 g of the title polymer.

The polymer used in the test was washed twice with 1000 mL each of water followed by 28.0 g of purified polymer twice with 800 mL each of methanol.

MAPTAC copoly-styrene (19%) crosslinked with 7.5% butanediol dimethacrylate crosslinking comonomer was prepared in a similar manner and by varying the ratio of starting monomers, copolymerized with 7% divinylbenzene Monomer cross-linked MAPTAC co-styrene (23%), MAPTAC co-styrene cross-linked with 6% divinylbenzene comonomer (30%), and cross-linked with 6% divinylbenzene comonomer Linked MAPTAC Co-Styrene (38%). Example 8. Poly(methacrylamidopropyltrimethylammonium chloride)copoly(vinylnaphthalene)

Preparation of (MAPTAC copolymerization-VN)

To a 1000 mL three-neck round bottom flask was added the following: methacrylamidopropyltrimethylammonium chloride (MAPTAC) (40 mL of a 50% aqueous solution, 21.0 g), divinylbenzene crosslinking comonomer (2.25 g), 2-vinylnaphthalene comonomer (10.5 g), and 2-propanol (320 mL). The resulting solution was clear. The reaction mixture was then heated to 65°C while degassing with nitrogen. When the solution reached 65°C, catalyst AIBN (0.50 g) was added. At this point the solution immediately began to turn cloudy, indicating that polymerization was in progress. The reaction was maintained at 65°C for 20 hours, then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 400 mL of distilled water. The mixture was stirred for 0.5 hours then filtered. Repeat the water wash once. The filter cake was slurried in 400 mL of methanol and stirred for 0.5 hours. The mixture was filtered and methanol slurrying was repeated once. Drying in vacuo gave 22.11 g, 65.5% of the title polymer.

MAPTAC Copolymer-VN (39%) crosslinked with 5% divinylbenzene crosslinking comonomer was prepared in a similar manner by varying the ratio of starting monomers. Example 9. Poly(methacrylamidopropyltrimethylammonium chloride)copoly(1-vinylimidazole)

Preparation of (MAPTAC copolymer-VI)

To a 1000 mL three-neck round bottom flask was added the following: methacrylamidopropyltrimethylammonium chloride (MAPTAC) (40 mL of a 50% aqueous solution, 21.0 g), divinylbenzene crosslinking comonomer (2.25 g), 1-vinylimidazole comonomer (12.54 g), and 2-propanol (300 mL). The resulting solution was clear. The reaction mixture was then heated to 65°C while degassing with nitrogen. When the solution reached 65°C, catalyst AIBN (0.50 g) was added. At this point the solution immediately began to turn cloudy, indicating that polymerization was in progress. The reaction was maintained at 65°C for 20 hours, then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 400 mL of distilled water. The mixture was stirred for 0.5 hours then filtered. Repeat the water wash once. The filter cake was slurried in 400 mL of methanol and stirred for 0.5 hours. The mixture was filtered and methanol slurrying was repeated once. Drying in vacuo yielded 7.34 g, 20.5% of the title polymer. Example 10. Poly(trimethylammonium chloride ethyl acrylate) copolymer(styrene)(TMAEAC copolymer-

Preparation of Sty)

To a 1000 mL three necked round bottom flask was added the following: trimethylammonium chloride ethyl acrylate (TMAEAC) (99.4 mL of a 50% aqueous solution, 53.0 g), divinylbenzene crosslinking comonomer (7.00 g), Styrene comonomer (40.0 g), and 2-propanol (800 mL). The resulting solution was clear. The reaction mixture was then heated to 65°C while degassing with nitrogen. When the solution reached 65°C, catalyst AIBN (1.50 g) was added. At this point the solution immediately began to turn cloudy, indicating that polymerization was in progress. The reaction was maintained at 65°C for 6 hours, cooled to 60°C and stirred for an additional 18 hours, then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 1000 mL of distilled water. The mixture was stirred for 0.5 hours then 800 mL of methanol was added and stirred for another 0.5 hours. The mixture was settled and the supernatant was decanted to give a residue of 750 mL. The residue was slurried with an additional 750 mL of methanol and stirred for 0.5 h. Methanol slurrying and decanting were repeated twice with 800 mL each of methanol. Then 800 mL of isopropanol was added, the mixture was stirred for 0.5 hours and filtered. Finally 600 mL of isopropanol was added and stirred for 0.5 hours. The filtrate was dried in vacuo to yield 49.2 g, 49.2% of the title polymer.

TMAEAC copoly-styrene (31%) crosslinked with 8% divinylbenzene crosslinking comonomer and crosslinked with 6% divinylbenzene crosslinking comonomer were prepared in a similar manner by varying the ratio of starting monomers. Linked TMAEAC co-styrene (46%). Example 11. Poly(trimethylammonium chloride ethyl methacrylate) copoly(styrene) (TMAEMC

  Preparation of Co-Styrene)

To a 1000 mL three necked round bottom flask was added the following: trimethylammonium chloride ethyl methacrylate (TMAEMAC) (38.8 mL of a 50% aqueous solution, 21.7 g), divinylbenzene crosslinking comonomer (3.72 g ), styrene comonomer (15.66 g), and 2-propanol (2500 mL). The resulting solution was clear. The reaction mixture was then heated to 65°C while degassing with nitrogen. When the solution reached 65°C, catalyst AIBN (0.50 g) was added. At this point the solution immediately began to turn cloudy, indicating that polymerization was in progress. After 2 hours the mixture became very viscous and another 100 mL of isopropanol was added. After 5 hours, the mixture became very viscous again, so another 100 mL of isopropanol was added. The reaction was maintained at 65°C for 6 hours, then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 1000 mL of distilled water. The mixture was stirred for 0.5 hours then transferred to a mixer and mixed for 5 minutes. The polymer slurry was filtered and 1000 mL of distilled water was added and the mixture was stirred for an additional 0.5 hours. The mixture was filtered and the filter cake was slurried twice with 500 mL each of methanol. The filtrate was dried in vacuo to yield 30.2 g, 75.9% of the title polymer.

TMAEMC co-poly-styrene (58%) cross-linked with 4% divinylbenzene cross-linking comonomer was prepared in a similar manner by varying the ratio of starting monomers, cross-linked with 4% divinylbenzene cross-linking comonomer Linked TMAEMC co-styrene (33%) and TMAEMC co-styrene crosslinked with 4% divinylbenzene crosslinking comonomer (24%). Example 12. Poly(methacrylamidopropyl-3-(trimethylammonium chloride)), copoly(2,3,4,5,6-

Preparation of pentafluorovinylstyrene) (MAPTAC copolymer-StyF ₅ )

To a 1000 mL three necked round bottom flask was added the following: methacrylamidopropyl-3-(trimethylammonium chloride) (MAPTAC) (24.5 mL of a 50% solution in water, 13.00 g), divinylbenzene Co-co-monomer (1.00 g), pentafluorostyrene comonomer (6.00 g), and 2-propanol (150 mL) and AIBN (0.50 g). The resulting solution was clear. The reaction mixture was then heated to 65°C while degassing with nitrogen. After a short time the solution started to become cloudy, indicating that polymerization was in progress. After 5 hours the mixture became very viscous, so an additional 100 mL of isopropanol was added. The reaction was maintained at 65°C for 24 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 500 mL of distilled water. The mixture was stirred for 0.5 hours, 500 mL of distilled water was added and the mixture was stirred for 0.5 hours. The polymer was filtered and the filter cake was slurried twice with 300 mL methanol each. The filtrate was dried in vacuo to give 7.74 g of the title polymer.

MAPTAC copoly-StyF ₅ (20%) cross-linked with 5% divinylbenzene cross-linking comonomer was prepared in a similar manner by changing the ratio of starting monomers, cross-linked with 5% divinylbenzene cross-linking comonomer Linked MAPTAC co- _StyF5 (40%) and MAPTAC co- _StyF5 crosslinked with 5% divinylbenzene crosslinking comonomer (45%). Example 13. Poly(methacrylamidopropyl-3-(trimethylammonium chloride)), copolymerized 2-(trimethylammonium chloride)

  Ammonium chloride) ethyl methacrylate copolymer-styrene (MAPTAC copolymer-

Preparation of TMAEMC copolymerization-Sty)

To a 1000 mL three necked round bottom flask was added the following: methacrylamidopropyl-3-(trimethylammonium chloride) (MAPTAC) (10.40 g of a 50% solution in water, 5.20 g), 2-(trimethylammonium ammonium chloride) ethyl methacrylate (TMAEMC) (4.86g, 70% aqueous solution, 3.40g), divinylbenzene crosslinking comonomer (1.00g), styrene comonomer (10.40g), 2 - Propanol (150 mL) and AIBN (0.50 g). The resulting solution was clear. The reaction mixture was then heated to 70°C while degassing with nitrogen. After a short time the solution started to become cloudy, indicating that polymerization was in progress. The reaction was maintained at 70°C for 24 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 500 mL of methanol. The mixture was stirred for 0.5 hours. The polymer slurry was filtered and 400 mL of distilled water was added and the mixture was stirred for an additional 0.5 hours. The mixture was filtered and water slurrying repeated. The mixture was filtered and the filter cake was slurried twice with 400 mL methanol each. The filtrate was dried in vacuo to yield 5.39 g of the title polymer.

MAPTAC copoly-TMAEMC (34%) copoly-Sty (36%) crosslinked with 5% divinylbenzene crosslinking comonomer was prepared in a similar manner by changing the ratio of starting monomers, and 5% divinylbenzene Cross-linked comonomer cross-linked MAPTAC-TMAEMC (31%) co-Sty (41%), MAPTAC co-TMAEMC (28%) cross-linked with 5% divinylbenzene cross-linked comonomer-Sty (46%), MAPTAC Co-TMAEMC (23%) cross-linked with 5% divinylbenzene cross-linking comonomer, Co-Sty (48%), cross-linked with 4% divinylbenzene cross-linking comonomer MAPTAC Co-TMAEMC (26%) Co-Sty (52%), MAPTAC Co-TMAEMC (17%) Co-Sty (53%) cross-linked with 4% divinylbenzene cross-linked comonomer, with 4 % MAPTAC co-TMAEMC (15%) cross-linked with divinylbenzene cross-linking comonomer (15%) Co-Sty (55%), MAPTAC co-TMAEMC cross-linked with 4% divinylbenzene cross-linking comonomer (13 %) Co-Sty (61.5%). Example 14. Poly(trimethylammonium chloride ethyl methacrylate copolymer-(isopropylacrylamide))

Preparation of (TMAEMAC copolymerization-IPA)

First, the preparation of comonomer isopropylacrylamide (IPA) is as follows:

Acryloyl chloride (63 mL, 70.2 g, 0.775 mol) was dissolved in tetrahydrofuran (200 mL) in a 1 L flask and placed in an ice bath. A solution containing isopropylamine (127.7 mL, 88.67 g, 1.50 mol) was added dropwise, keeping the temperature at 5-15°C. The solution was stirred for 10 minutes and the solid isopropylamine hydrochloride was filtered off. The solvent was removed in vacuo from the mother liquor to give an almost colorless oil which solidified on standing and was used without further purification in the preparation of the title copolymer below.

To a 1000 mL three necked round bottom flask was added the following: trimethylammonium chloride ethyl methacrylate (76.5 mL of a 50% aqueous solution, 41.18 g, 0.213 mol), methylenebisacrylamide crosslinking comonomer ( 2.40 g), IPA comonomer (4.52 g, 0.070 mol), and water (200 mL). The resulting solution was clear. The reaction mixture was stirred while degassing with nitrogen. A catalyst consisting of potassium persulfate (0.3 g) and potassium pyrophosphite (0.3 g) was added while the solution was degassing. Polymerization started after 2 minutes and gelled after 3 minutes.

The next morning, the gum was transferred to a mixer and 1000 mL of water was added. The polymer absorbed all the water after mixing for a few seconds. The swollen polymer was dehydrated by mixing several batches with isopropanol several times. The resulting polymer was filtered and washed on the funnel with isopropanol, and the filtrate was dried in vacuo to yield 36.8 g of the title copolymer. Example 15. Poly(methacrylamidopropyl-3-(trimethylammonium chloride))co-(vinylpyridine)

Preparation of (MAPTAC copolymerization-VP)

To a 1000 mL three-neck round bottom flask was added the following: methacrylamidopropyl-3-(trimethylammonium chloride) (MAPTAC) (40 mL of a 50% solution in water, 21.0 g), divinylbenzene cross-linked Comonomer (2.25 g), vinylpyridine (14.0 g, 0.133 mol), concentrated hydrochloric acid (11 mL, 0.133 mol), 2-propanol (300 mL), and AIBN (0.67 g). The resulting solution was clear. Next, the reaction mixture was heated to 60°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that polymerization was in progress. The reaction mixture was maintained at 60°C for 20 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 1000 mL of distilled water. The mixture was stirred for 1 hour. The polymer slurry was filtered, washed with methanol on the funnel, and then slurried in 600 mL of methanol for 1 hour. Filtration and air drying yielded 20.4 g of copolymer. Example 16. Poly(trimethylammonium chloride ethyl methacrylate) copolymer-(p-fluorostyrene)

Preparation of (TMAEMC Copolymerization-F ₁ Sty)

To a 500 mL flask was added the following: trimethylammonium chloride ethyl methacrylate (TMAEMC) (11.0 g of a 70% solution in water, 7.70 g), divinylbenzene crosslinking comonomer (0.50 g), p-fluoro Styrene comonomer (4.00 g), 2-propanol (125 mL) and AIBN (0.25 g). The resulting solution was clear. Next, the reaction mixture was heated to 65°C while degassing with nitrogen. The solution immediately became cloudy, indicating that polymerization was in progress. The reaction was maintained at 65°C for 6 hours, then cooled to room temperature.

The solvent was removed by decantation and the polymer was immediately slurried in 250 mL of distilled water. The mixture was stirred for 0.5 hours then decanted. This was slurried 3 times with water. Finally, the polymer was slurried with 400 mL of methanol. Filtration and vacuum drying afforded 5.42 g, 44.4% of the title copolymer.

TMAEMC co-F ₁ Sty (24%) crosslinked with 4% divinylbenzene crosslinking comonomer was prepared in a similar manner by varying the ratio of starting monomers. Example 17. Poly(methacrylamidopropyl-3-(trimethylammonium chloride))copoly-(hexafluoromethylpropane

Butyl acrylate) (MAPTAC copolymerization-F ₆ BMA)

To a 1000 mL three necked round bottom flask was added the following: methacrylamidopropyl-3-(trimethylammonium chloride) (MAPTAC) (28.5 mL of a 50% solution in water, 15.0 g), divinylbenzene Co-co-monomer (1.00 g), butyl hexafluoromethacrylate (4.00 g), 2-propanol (150 mL) and AIBN (0.50 g). The resulting solution was clear. Next, the reaction mixture was heated to 60°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. The reaction was maintained at 60°C for 24 hours, then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then slurried with 500 mL of distilled water. The mixture was stirred for 1 hour. The polymer slurry was filtered and reslurried with water. The polymer was slurried in 500 mL of methanol for 1 hour and filtered, and repeated once. Finally the mixture was slurried in 400 mL of isopropanol and stirred overnight. Filtration and air drying yielded 7.52 g of the title copolymer. Example 18. Poly(trimethylammonium chloride ethyl acrylate) copoly-(isopropyl hexafluoroacrylate)

Preparation of (TMAEAC copolymer- _F6IA )

To a 1000 mL three-neck round bottom flask was added the following: trimethylammonium chloride ethyl acrylate (30.0 mL of a 50% solution in water, 15.0 g), divinylbenzene crosslinking comonomer (1.00 g), _F6IPA (4.00g), AIBN (0.50g) and 2-propanol (150mL). The resulting solution was clear. The reaction mixture was stirred while degassing with nitrogen and heated to 60°C. After 18 hours the reaction mixture was allowed to cool to room temperature and the solvent was removed by decantation. The remaining polymer was slurried in 400 mL of water, stirred for 1 hour and filtered. Slurry again with water and twice with methanol. Finally, the polymer was slurried in 200 mL of isopropanol, stirred for 2 hours and filtered. Air drying gave 5.59 g of the title polymer. Example 19. Poly(methacrylamidopropyl-3-(trimethylammonium chloride))copoly-(heptadecafluoromethyl

Preparation of Decyl Acrylate)(MAPTAC Copolymerization-F ₁₇ DecMA)

To a 1000 mL three necked round bottom flask was added the following: methacrylamidopropyl-3-(trimethylammonium chloride) (MAPTAC) (28.5 mL of a 50% solution in water, 15.0 g), divinylbenzene Co-co-monomer (1.00 g), heptadecylfluorodecyl methacrylate (4.00 g), 2-propanol (1 50 mL) and AIBN (0.40 g). The resulting solution was clear. Then, the reaction mixture was heated to 65°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. After 4 hours the reaction mixture had become very thick and another 100 mL of isopropanol was added and the reaction was maintained at 65°C for 18 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 600 mL of distilled water. The mixture was stirred for 1 hour. The polymer slurry was filtered and slurried once more with water. The mixture was then slurried in 500 mL of methanol for 1 hour and filtered. Air drying gave 17.73 g of the title polymer. Example 20. Poly(methacrylamidopropyl-3-(trimethylammonium chloride))copoly-(2-(trimethylammonium chloride)

Ammonium chloride) ethyl acrylate), copolymer-styrene (MAPTAC copolymer-TMAEAC copolymer

Preparation of poly-Sty)

To a 1000 mL three-neck round bottom flask was added the following: methacrylamidopropyl-3-(trimethylammonium chloride) (MAPTAC) (10.00 g in 50% water, 5.00 g), 2-(trimethylammonium chloride) ammonium chloride) ethyl acrylate (TMAEAC) (6.00 g in 50% aqueous solution, 3.00 g), divinylbenzene crosslinking comonomer (1.00 g), styrene (11.00 g), 2-propanol (150 mL ) and AIBN (0.25g). The resulting solution was clear. Then, the reaction mixture was heated to 70°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. The reaction was maintained at 70°C for 24 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 500 mL of methanol. The mixture was stirred for 0.5 hours. Settling and decanting the polymer slurry. 200 mL of distilled water was added and the mixture was stirred for 0.5 hours. The mixture was decanted and then reslurried with 400 mL of water. The mixture was decanted and the polymer was slurried twice with 200 mL methanol each. Filtration and air drying afforded 2.76 g of the title copolymer.

MAPTAC co-TMAEAC (10%) co-Sty (60%) crosslinked with 5% divinylbenzene crosslinking comonomer was prepared in a similar manner by varying the ratio of starting monomers. Example 21. Poly(2-(trimethylammonium chloride) ethyl acrylate), copoly-(2,3,4,5,6-pentafluorostyrene)

Preparation of (TMAEAC copolymerization-StyF ₅ )

To a 1000 mL three necked round bottom flask was added the following: 2-(Trimethylammonium chloride) ethyl acrylate (TMAEAC) (24.0 mL of a 50% solution in water, 13.00 g), divinylbenzene crosslinking comonomer ( 1.00 g), pentafluorostyrene (6.00 g), 2-propanol (150 mL) and AIBN (0.50 g). The resulting solution was clear. Then, the reaction mixture was heated to 65°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. After 2 hours the mixture was already very thick, so 100 mL of isopropanol was added. The reaction was maintained at 65°C for 22 hours, then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 400 mL of distilled water. The mixture was stirred for 0.5 hours. The polymer slurry was filtered and 600 mL of distilled water was added, and the mixture was stirred for 0.5 hours. The mixture was filtered and the filter cake was slurried in 400 mL of methanol. Filtration and air drying yielded 7.26 g of the title copolymer.

TMAEAC co-StyF ₅ (20%) crosslinked with 5% divinylbenzene crosslinking comonomer was prepared in a similar manner by varying the ratio of the starting monomers. Example 22. Poly(2-(trimethylammonium chloride)ethyl methacrylate), copoly-(2,3,4,5,6-pentafluorobenzene

Preparation of ethylene) (TMAEMC copolymerization-StyF ₅ )

To a 1000 mL three necked round bottom flask was added the following: 2-(Trimethylammonium chloride) ethyl methacrylate (TMAEMC) (19.52 mL of a 70% solution in water, 13.66 g), divinylbenzene cross-linked copolymer solid (1.00g), pentafluorostyrene (9.18g), 2-propanol (150mL) and AIBN (0.40g). The resulting solution was clear. Then, the reaction mixture was heated to 70°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. After 1.5 hours the mixture was already very thick, so 50 mL of isopropanol was added. The reaction was maintained at 70°C for 5 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 500 mL of distilled water. The mixture was stirred for 0.25 hours. The polymer slurry was filtered and 500 mL of distilled water was added, and the mixture was stirred for 0.25 hours. The polymer was slurried once more with water. The mixture was filtered, and the filter cake was slurried three times in 300 mL portions of methanol. Filtration and air drying afforded 1.26 g of the title copolymer.

TMAEMC copoly-StyF ₅ (24%) cross-linked with 4% divinylbenzene cross-linking comonomer and cross-linked with 4% divinylbenzene cross-linking comonomer were prepared in a similar manner by changing the ratio of starting monomers Linked TMAEMC co-StyF ₅ (39%). Example 23. Preparation of poly(ethyleneimine)

Polyethyleneimine (120 g of a 50% aqueous solution; Scientific Polymer Products) was dissolved in water (250 mL). Epichlorohydrin (22.1 mL) was added dropwise. The solution was heated to 60°C for 4 hours. Afterwards, a colloid is formed. The gel was removed, taken up with water (1.5 L), and the solid was filtered off, rinsed three times with water (3 L) and twice with isopropanol (3 L). The resulting gel was dried in a vacuum oven to yield 81.2 g of the title polymer. Example 24. Poly(methacrylamidopropyl-3-(trimethylammonium chloride)), copoly-(2-(trimethylammonium chloride)

  Ammonium chloride) ethyl methacrylate), copolymer-(2,3,4,5,6-pentafluorostyrene)

Preparation of (MAPTAC Copolymerization-TMAEMC Copolymerization-StyF ₅ )

To a 1000 mL three-neck round bottom flask was added the following: methacrylamidopropyl-3-(trimethylammonium chloride) (MAPTAC) (10.00 g in 50% water, 5.00 g), 2-(trimethylammonium chloride) ammonium chloride) ethyl methacrylate (TMAEMC) (5.71 g in 70% aqueous solution, 4.00 g), divinylbenzene crosslinking comonomer (1.00 g), pentafluorostyrene (10.00 g), 2- Propanol (1 50mL) and AIBN (0.50g). The resulting solution was clear. Then, the reaction mixture was heated to 70°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. The reaction was maintained at 70°C for 24 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 500 mL of methanol. The mixture was stirred for 0.25 hours. The slurry polymer was filtered and slurried three times with 300 mL of water each time. The final slurry of polymer was blended for 5 minutes. The mixture was filtered, and the filter cake was slurried twice with 300 mL of methanol each. Filtration and vacuum drying yielded 9.74 g of copolymer. Example 25. Poly(2-(trimethylammonium chloride) ethyl acrylate), copoly-(2-(trimethylammonium chloride) formazan

Ethyl Acrylate), Co-Styrene (TMAEAC Co-TMAEMC Co-polymer

-Sty) preparation

To a 1000 mL three necked round bottom flask was added the following: 2-(Trimethylammonium chloride) ethyl acrylate (TMAEAC) (6.00 g of a 50% solution in water, 3.00 g), 2-(Trimethylammonium chloride) Ethyl methacrylate (TMAEMC) (4.29 g in 70% water, 3.00 g), divinylbenzene crosslinking comonomer (1.00 g), styrene (13.00 g), 2-propanol (150 mL) and AIBN (0.50g). The resulting solution was clear. Then, the reaction mixture was heated to 70°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. The reaction was maintained at 70°C for 24 hours and then cooled to room temperature.

The resulting polymer was decanted and immediately slurried in 500 mL of methanol. The mixture was stirred for 0.5 hours. The slurry polymer was filtered and 500 mL of distilled water was added. The mixture was stirred for 0.5 hour and mixed for 10 minutes. The mixture was settled and the water was decanted. Repeat the water slurrying twice, each time with 400 mL of methanol to decant the residue, and each time to settle and decant. Drying in vacuo yielded 8.03 g of the title copolymer. Example 26. Poly(methacrylamidopropyl-3-(trimethylammonium chloride)), copoly-(2-(trimethylammonium chloride)

  Ammonium chloride) ethyl acrylate), copolymer-(2,3,4,5,6-pentafluorostyrene) (MAPTAC

Preparation of Co-TMAEAC Co-StyF ₅ )

To a 1000 mL three-neck round bottom flask was added the following: ethyl methacrylate-3-(trimethylammonium chloride) (MAPTA) (8.00 g, 50% in water, 4.00 g), 2-(trimethylammonium chloride Ammonium chloride) ethyl acrylate (TMAEMA) (6.00 g in 50% aqueous solution, 3.00 g), divinylbenzene crosslinking comonomer (1.00 g), pentafluorostyrene (12.00 g), 2-propanol (150 mL ) and AIBN (0.50 g). The resulting solution was clear. Then, the reaction mixture was heated to 70°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. The reaction was maintained at 70°C for 24 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 400 mL of methanol. The mixture was stirred for 0.5. The slurry polymer was filtered and slurried twice with 250 mL of water each time. The final slurry of polymer was mixed for 5 minutes. The mixture was filtered and then slurried twice with 250 mL of methanol each. The filtrate was dried in vacuo to yield 7.80 g of copolymer. Example 27. Poly(2-(trimethylammonium chloride) ethyl acrylate), copoly-(2-(trimethylammonium chloride) formazan

ethyl acrylate), copolymer-(2,3,4,5,6-pentafluorostyrene) (TMAEAC copolymer

-TMAEMC copolymerization-Sty F ₅ ) Preparation

To a 1000 mL three necked round bottom flask was added the following: 2-(Trimethylammonium chloride) ethyl acrylate (TMAEAC) (6.00 g of a 50% solution in water, 3.00 g), 2-(Trimethylammonium chloride) Ethyl methacrylate (TMAEMC) (4.29 g, 70% aqueous solution, 3.00 g), divinylbenzene crosslinking comonomer (1.00 g), pentafluorostyrene (13.00 g), 2-propanol (150 mL ) and AIBN (0.50 g). The resulting solution was clear. Then, the reaction mixture was heated to 70°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. The reaction was maintained at 70°C for 24 hours and then cooled to room temperature.

The resulting polymer was decanted and immediately slurried in 400 mL of methanol. The mixture was stirred for 0.5 hours. The slurry polymer was filtered and then slurried twice with 200 mL of water each time. The second slurry polymer was mixed for 5 minutes. The mixture was filtered and slurried twice with 200 mL of methanol each. Drying in vacuo yielded 6.87 g of the title copolymer. Example 28. Poly(methacrylamidopropyltrimethylammonium chloride)copoly(4-vinylbiphenyl)

Preparation of (MAPTAC copolymerization-VBPh)

To a 1000 mL three-neck round bottom flask was added the following: methacrylamidopropyltrimethylammonium chloride (MAPTAC) (10.49 g of a 50% aqueous solution, 0.0475 mol), 4-vinylbiphenyl (VBPh) ( 9.01 g, 0.050 mol), divinylbenzene crosslinking comonomer (1.47 g), 2-propanol (150 mL), polymerization initiator AIBN (0.25 g). The resulting mixture contained insoluble VBPh (dissolved upon heating). Then, the reaction mixture was heated to 70°C while degassing with nitrogen. After a short time the solution became cloudy, indicating that the polymerization reaction was in progress. The reaction was maintained at 70°C for 24 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 200 mL of methanol followed by stirring for 1 hour. The slurry polymer was filtered and the methanol slurrying step was repeated. The polymer was then slurried twice with 200 mL of water each time. The resulting mixture was filtered and the filter cake was then slurried twice with 200 mL each of methanol. The resulting mixture was filtered and dried under vacuum to yield 9.59 g of copolymer. Example 29. Poly(methacrylamidopropyltrimethylammonium chloride)copoly(4-vinylbiphenyl)

Preparation of (MAPTAC copolymerization-VA)

To a 1000 mL three necked round bottom flask was added the following: methacrylamidopropyltrimethylammonium chloride (MAPTAC) (10.49 g of a 50% aqueous solution, 0.0475 mol), 4-vinylanisole (VA) ( 6.71 g, 0.050 mol), divinylbenzene crosslinking comonomer (1.30 g), 2-propanol (200 mL), polymerization initiator AIBN (0.40 g). The resulting clear solution was then heated to 70°C while degassing with nitrogen. After a few hours the solution became cloudy, indicating that polymerization was in progress. The reaction was maintained at 70°C for 36 hours and then cooled to room temperature.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 200 mL of methanol followed by stirring for 1 hour. Filter slurry polymer. The polymer was then slurried twice with 200 mL each of water. The resulting mixture was filtered and the filter cake was slurried with 200 mL of methanol followed by 200 mL of isopropanol. The resulting mixture was filtered and dried under vacuum to yield 5.19 g of copolymer. Example 30. Poly[(N-(4-methylstyrene)-N'-(3-trimethylammonium chloride-2-hydroxypropyl)piperazine]

Preparation of

The first step is the reaction to prepare 4-(piperazinylmethyl)styrene.

To a 500 mL flask was added vinylbenzyl chloride (7.63 g, 0.050 mol), piperazine (8.61 g, 0.100 mol) and isopropanol (50 mL). The resulting mixture was heated at 70°C for 45 minutes, then slowly cooled to room temperature to form a slurry of crystalline material. The slurry was placed in the refrigerator for about 3 hours, then filtered. The solid piperazine hydrochloride was dried in vacuo, then weighed (5.55 g) and discarded. The mother liquor was concentrated to about 25 mL on a rotary evaporator and ethyl acetate (50 mL) was added. The resulting mixture was placed in the refrigerator for about 10 minutes, then the piperazine hydrochloride obtained a second time was filtered and discarded. Evaporation of the mother liquor to dryness on a rotary evaporator yielded 10.35 g of crude 4-(piperazinemethyl)styrene, which was used to prepare the following N-(4-methylstyrene)-N'-(3-trimethyl Ammonium chloride-2-hydroxypropyl)piperazine and without further purification. To a 500 mL flask was added 4-(piperazinemethyl)styrene (10.35 g, about 0.45 mol), glycidyltrimethylammonium chloride (7.58 g, 0.045 mol) and isopropanol (50 mL). The resulting mixture was heated to 60°C and stirred for 20 hours, then cooled to room temperature and used in the following polymerization without further purification.

Add divinylbenzene crosslinking comonomer (0.93 g) to 0.40 mol N-(4-methylstyrene)-N'-(3-trimethylammonium chloride-2-hydroxypropyl)piperazine middle. The resulting solution was degassed with nitrogen, and then AIBN (0.20 g), a polymerization initiator, was added. The temperature was raised to 70°C and degassed with nitrogen was continued for 3 hours, at which time a large amount of cross-linked polymer precipitated. The mixture was then cooled to 40°C and filtered.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 200 mL of methanol followed by stirring for 1 hour. The slurry polymer was filtered and the methanol slurrying step was repeated. The polymer was slurried twice with 200 mL of water each time. Then filtered, the filter cake was slurried twice with 200 mL of methanol each time, and vacuum-dried to obtain 7.90 g of copolymer. Example 31. Poly(N-(4-methylstyrene)-N'-(3-trimethylammonium chloride-2-hydroxypropyl)piperazine,

  Preparation of Copolystyrene

To 0.022 mol of N-(4-methylstyrene)-N'-(3-trimethylammonium chloride-2-hydroxypropyl)piperazine (prepared as described in Example 30) was added styrene copolymerized monomer monomer (2.29 g, 0.022 mol) and divinylbenzene crosslinking comonomer (0.50 g, 0.004 mol). The resulting solution was degassed with nitrogen, and then AIBN (0.3 g), a polymerization initiator, was added. The temperature was raised to 70°C, degassing with nitrogen was continued and allowed to stand for 4 hours, at which time a large amount of cross-linked polymer precipitated. Then 25 mL of isopropanol was added and heating was continued for 19 hours. Afterwards, the mixture was cooled to room temperature and filtered to obtain a solid polymer.

The resulting polymer was filtered and washed on the funnel with isopropanol, then immediately slurried in 200 mL of methanol. Next, the mixture was stirred for 0.5 hours. Filter the slurry polymer, and slurry the polymer with 250 mL of water each time, twice in total. The mixture was filtered, and the filter cake was slurried in 200 mL of methanol, filtered, and then slurried in 200 mL of isopropanol. Filtration and vacuum drying yielded 4.98 g of copolymer.

A styrene:quaternary ammonium monomer containing a 2:1 molar ratio was similarly prepared. Example 32. Preparation of poly(N-(3-trimethylammonium chloride-2-hydroxypropyl)-4-aminostyrene

The first step is to prepare 4-aminomethylstyrene as described below.

To a 250 mL flask was added vinylbenzyl chloride (7.63 g, 0.050 mol), concentrated ammonia (9.8 mL) and isopropanol (40 mL). The mixture was stirred for 1 week, at which time a large amount of crystalline material (ammonium chloride) precipitated. The solid was filtered off and washed with isopropanol. The mother liquor was evaporated on a rotary evaporator until there was no smell of ammonia. Isopropanol (50 mL) was added and the mixture was refrigerated for several hours. After freezing, the 4-aminomethylstyrene ammonium chloride which had precipitated was filtered off to give 4-aminomethylstyrene which was used without further purification.

Add 4-aminomethylstyrene (0.050mol), glycidyltrimethylammonium chloride (7.62g, 0.050mol) and water (about 2mL) into a 500mL flask to form a solution, and add divinyl cross-linking copolymer Monomer (0.98 g). The resulting solution was heated at 70°C for 5 hours, after which a small amount of water (about 5-10 mL) was added to dissolve some of the precipitated salts. The polymerization initiator AIBN (0.20 g) was added while degassing the solution with nitrogen. The reaction mixture had become very thick by this point and it was necessary to add isopropanol to make the polymer stirrable.

After stirring at 70°C for about 16 hours, the mixture was cooled to room temperature and filtered. The resulting polymer was washed with methanol on the funnel and immediately slurried in 200 mL of methanol. Next, the resulting mixture was stirred for 1 hour. The slurry polymer was filtered and the slurrying process was repeated one more time with methanol. The polymer was then slurried with two 200 mL portions of methanol. The mixture was filtered and the filter cake was slurried in 200 mL of methanol. Filtration and vacuum drying yielded 8.68 g of polymer. Example 33. Poly(bismethacrylamide) crosslinked with 1-iodooctane alkylating agent

  Alkylation of methylaminopropyl methacrylamide

Poly(dimethylaminopropylmethacrylamide) (1.0 g) cross-linked with methylenebismethacrylamide prepared by the method described in Example 5 was suspended in methanol (100 mL), and sodium hydroxide was added (0.2g). After stirring for 15 minutes, 1-iodooctane (1.92 mL) was added, and the mixture was stirred at 60°C for 20 hrs. Then, the mixture was cooled and the solid was filtered off. The solid was washed by suspending it in isopropanol (500 mL). Afterwards, it was stirred for 1 hour and collected by filtration. The washing process was repeated twice with aqueous sodium chloride (500 mL of a 1M solution), twice with water (500 mL), and once with isopropanol (500 mL). Drying in a vacuum oven at 50°C for 24 hours yielded 0.1 g of the alkylated product. Example 34. Poly(bismethacrylamide) crosslinked with 1-iodooctane alkylating agent

  Methylaminopropyl acrylamide) Alkylation

Poly(dimethylaminopropylacrylamide) (10 g) prepared by the method described in Example 4 and crosslinked with methylenebismethacrylamide (10 g) was alkylated according to the method described in Example 33 to obtain 2.95 g of alkanes. base products. Example 35. Preparation of poly(2-(methacrylamido)ethyltrimethylammonium iodide)copoly-styrene

Prepare

The first step is to prepare 2-(N',N'-dimethylamino)-N-ethylmethacrylamide hydrochloride as described below.

To a 1000 mL flask was added methacryloyl chloride (52.3 g, 0.5 mol) and tetrahydrofuran (300 mL). The solution was cooled below 10°C, then N,N-dimethylaminoethylamine (30.5 g, 0.35 mol) in tetrahydrofuran (100 mL) was added dropwise while maintaining the temperature at 8-10°C. After the addition was complete, the mixture was filtered, washed with cold tetrahydrofuran, and dried in vacuo to obtain 65.69 g of 2-(N',N'-dimethylamino)-N-ethylmethacrylamide hydrochloride.

The next step is to prepare 2-(methacrylamido)ethyltrimethylammonium iodide as described below.

Potassium hydroxide (15.4 g, 0.24 mol) and methanol (240 mL) were put into a 500 mL flask, and the mixture was stirred well to completely dissolve potassium hydroxide. 2-(N',N'-dimethylamino)-N-ethylmethacrylamide hydrochloride (46.35 g, 0.24 mol) was added to the solution, and the resulting mixture was stirred for 0.5 hours. The mixture was filtered to remove potassium chloride. The filtrate was concentrated on a rotary evaporator. Isopropanol (400 mL) and methyl iodide (18.7 mL, 42.6 g, 0.30 mol) were added to the concentrated filtrate, and the mixture was stirred at room temperature overnight. The next morning, the solid product was filtered, washed with isopropanol, and dried in vacuo to obtain 61.08 g of 2-(methacrylamido)ethyltrimethylammonium iodide as a white crystalline solid.

Next, 2-(methacrylamido)ethyltrimethylammonium iodide (12.24g, 0.050mol), styrene (5.2g, 0.050mol), divinylbenzene crosslinking comonomer (0.65g , 0.005mol), isopropanol (150mL), water (20mL), and polymerization initiator AIBN (0.4g) were added to a 1000mL flask. The resulting solution was degassed with nitrogen while heating to 70°C. The solution was then stirred at 70°C under nitrogen for 24 hours, after which it was cooled to room temperature. At this point, the solvent was decanted, then 200 mL of methanol was added to the flask to form a slurry and stirred overnight. The product was filtered, then added to a blender and mixed with 500 mL of water. The resulting mixture was stirred for 15 minutes, then filtered. The remaining solid material was washed successively with water (200 mL) and methanol (200 mL). Filtration and vacuum drying afforded 3.22 g of the title polymer. Polymer Test A. Preparation of Artificial Intestinal Fluid Test Method 1

Sodium carbonate (1.27 g) and sodium chloride (1.87 g) were dissolved in 400 mL of distilled water. To this solution was added a pure bile acid mixture consisting of taurocholic acid (0.138g, 0.24mmol), glycocholic acid (0.292g, 0.60mmol), glycodeoxycholic acid (0.085g, 0.18mmol) and glycine Composition of glycochenodeoxycholic acid (0.085g, 0.18mmol). The pH of the solution was adjusted to 7.20 with acetic acid. This solution was used for testing various polymers. The concentration of total bile salts in this solution is 3 millimolar, which is approximately equal to that of normal body fluid in the duodenum.

The polymer tests were as follows.

Add 0.25 g of the polymer and 20 mL of the artificial small intestine fluid prepared above into a 40 mL centrifuge tube. The mixture was stirred for 3 hours in a water bath maintained at 37°C. The mixture was centrifuged and the slightly cloudy supernatant was filtered. The filtrates were analyzed for total 3-hydroxysteroid content by enzymatic assay with 3a-hydroxysteroid dehydrogenase (described below). Test method 2

Sodium carbonate (1.27 g) and sodium chloride (1.87 g) were dissolved in 400 mL of distilled water. Glycocholic acid (1.95 g, 4.0 mmol) or glycochenodeoxycholic acid (1.89 g, 4.0 mmol) was added to this solution to make a 10 mM solution. The pH of the solution was adjusted to 6.8 with acetic acid. These stock solutions were used for testing of various polymers.

The polymer tests were as follows.

Into a 14 mL centrifuge tube was added 10 mg of polymer and 10 mL of bile salt solution prepared from the 10 mM stock solution (prepared as above) at a concentration of 0.1-10 mM, and appropriate amount of bile salt-free buffer. The mixture was stirred for 3 hours in a water bath maintained at 37°C. Filter the mixture. Filtrates were analyzed for total 3-hydroxysteroid content by enzymatic assay with 3α-hydroxysteroid dehydrogenase (described below).

Enzymatic determination of total bile salt content

Four stock solutions were prepared.

Solution 1: Tris-HCl buffer containing 0.133M Tris, 0.666mM EDTA,

  pH9.5.

Solution 2: Hydrazine hydrate solution, containing 1M hydrazine hydrate at pH 9.5.

Solution 3: NAD+ solution, containing 7mM NAD+, pH 7.0.

Solution 4: HSD solution containing 2 units/mL of Tris-HCl buffer (0.03M Tris,

1mM EDTA), pH7.2.

Add 1.5 mL of solution 1, 1.0 mL of solution 2, 0.3 mL of solution 3, 0.1 mL of solution 4 and 0.1 mL of the supernatant/filtrate from the above polymer assay in a 3 mL cuvette. The solution was placed in a UV-VIS spectrophotometer and its NADH absorption (O.D.) at 340 nm was measured. Bile salt concentrations were determined from the artificial intestinal fluid dilution calibration curve prepared above.

All of the aforementioned polymers participated in one or both of the above tests and all were effective in removing bile salts from artificial intestinal fluid. use

The polymers of the present invention can be administered orally to a patient at a dose of about 1 mg/kg/day to about 10 g/kg/day. The specific dosage will depend on the circumstances of each patient, such as the patient's weight and the range of bile salts to be removed. The polymers can be administered in hydrated or non-hydrated form and, if desired, flavored to increase patient acceptance. In addition, ingredients that can be added include artificial colors.

Examples suitable for administration include pills, tablets, sachets and powders (eg sprayed on food). These pills, tablets, sachets, or powders may be coated with a protective substance that protects the composition from gastric acid in the patient's stomach long enough to reach the patient's small intestine without being broken down. The polymer may be administered alone or with a pharmaceutically acceptable carrier material such as magnesium carbonate or lactose, or the polymer forms micelles with phospholipids.

Other specific descriptions are included in the claims of the present invention.

Claims (29)

1. A polymer composition for the manufacture of a medicament for removing bile salts from a patient by ion exchange, comprising a therapeutically effective amount of the reaction product of: (a) one or more crosslinked polymers having repeating units of the formula:

Or its salt and its copolymer, wherein n is an integer; R ¹ is H or C ₁ -C ₈ alkyl; M is or -ZR ² ; Z is O, NR ³ , S, or (CH ₂ ) _m ; m=0-10; R ³ is H or C ₁ -C ₈ alkyl; and R ² is or

wherein P=0-10, and R ⁴ and R ⁵ are H; R ⁶ is H, C ₁ -C ₈ alkyl, or aryl; and (b) at least one alkylating agent, wherein the polymer is cross-linked by a polyfunctional cross-linking agent, the amount of the agent accounts for 1-25% by weight of the total monomer weight; The chemical reagent has the formula RX, wherein R comprises C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ hydroxyalkyl, C ₁ -C ₂₀ aralkyl, C ₁ -C ₂₀ alkylammonium, or C ₁ -C ₂₀ Alkylamido, and X includes one or more electrophilic leaving groups. 2. The polymer composition of claim 1, wherein the polymer is crosslinked by a multifunctional crosslinking comonomer. 3. The polymer composition of claim 2, wherein the crosslinking comonomer is 2.5-20% by weight of the total monomers. 4. A polymer composition for the manufacture of a medicament for the removal of bile salts from a patient by ion exchange, comprising a therapeutically effective amount of the reaction product of (a) one or more crosslinked polymers comprising A repeating unit represented by the formula:

or a salt thereof and a copolymer thereof, wherein n is an integer, p=0-10, R ¹ is H or a C1 to C8 alkyl group, R ⁴ and R ⁵ are each H, C1 to C8 alkyl or aryl (b) at least two alkylating agents, wherein (i) one of said alkylating agents has the formula RX, wherein R is C1 to C20 alkyl, and X is one or more electrophilic leaving groups another said alkylating agent has the formula R'X, wherein R' is a C1 to C20 alkylammonium group and X is one or more electrophilic leaving groups; or (ii) a Said alkylating agent has the formula RX, wherein R is a C1 to C20 alkyl group, X is one or more electrophilic leaving groups, and another said alkylating agent has the formula R'X, wherein R' is a C1 to C20 hydroxyalkyl group, X is one or more electrophilic leaving groups; (iii) one of said alkylating agents is a C1 to C20 dihaloalkane, and the other said alkane The alkylating reagent is a C1 to C20 alkylammonium salt. 5. The polymer composition according to claim 4, wherein said repeat unit (a) has the formula or its salt or its copolymer. 6. The polymer composition according to claim 4, wherein said repeat unit (a) has the formula or its salt or its copolymer. 7. A polymer composition for the manufacture of a medicament for the removal of bile salts from a patient by ion exchange, comprising a therapeutically effective amount of the reaction product of (a) one or more crosslinked polymers comprising A repeating unit represented by the formula:

or a salt thereof or a copolymer thereof, wherein ^R is H or C1 to C8 alkyl, n is an integer, and p=0-10; and (b) at least two alkylating agents, wherein (i) one of the Said alkylating agent has the formula RX, wherein R is a C1 to C20 alkyl group, X is one or more electrophilic leaving groups, and another said alkylating agent has the chemical formula R'X, wherein R' is a C1 to C20 alkylammonium group and X is one or more electrophilic leaving groups; or (ii) a said alkylating agent has the formula RX, wherein R is a C1 to C20 alkyl , X is one or more electrophilic leaving groups, another said alkylating agent has the chemical formula R'X, wherein R' is C1 to C20 hydroxyalkyl, X is one or more electrophilic Leaving group; (iii) one of said alkylating agents is a C1 to C20 dihaloalkane, and the other said alkylating agent is a C1 to C20 alkylammonium salt. 8. A polymer composition for the manufacture of a medicament for the removal of bile salts from a patient by ion exchange, comprising a therapeutically effective amount of the reaction product of (a) one or more crosslinked polymers comprising A repeating unit represented by the formula:

or a salt thereof or a copolymer thereof, wherein R ¹ is H or C1 to C8 alkyl, n is an integer, and p=1-10; (b) at least one alkylating agent having the formula RX, where R includes C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ hydroxyalkyl, C ₁ -C ₂₀ aralkyl, C ₁ -C ₂₀ alkylammonium, or C ₁ -C ₂₀ alkylamido , and X includes one or more electrophilic leaving groups. 9. The polymer composition of claim 1, wherein said repeat unit (a) has the formula

Or its salt and its copolymer, wherein Z is NR ³ or (CH ₂ ) _m , R ² is or And R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , n, m, and p are as defined in claim 1 . 10. The polymer composition of claim 1, 7 or 8, wherein said polymer further comprises one or more exchangeable balances. 11. The polymer composition of claim 10, wherein at least one of the balances comprises Cl ⁻ , Br ⁻ , CH ₃ OSO ₃ ⁻ , HSO ₄ ⁻ , SO ₄ ²⁻ , HCO ₃ ⁻ , CO ₃ ^2- , acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, amino acid derivatives, nucleotides, lipids, Phospholipids. 12. The polymer composition of claim 11, wherein said X comprises a halide, epoxide, mesylate, or mesylate group. 13. The polymer composition of claim 12, wherein the alkylating agent comprises a _C4 - _C20 alkyl halide. 14. The polymer composition of claim 12, wherein the alkylating agent comprises a _C1 - _C20 alkyl ammonium halide. 15. The polymer composition according to claim 12, wherein said alkylating agent is C ₁ -C ₂₀ dihaloalkyl, C ₁ -C ₂₀ hydroxyalkyl halide, C ₁ -C ₂₀ aralkyl halogen, C ₁ -C ₂₀ alkyl epoxy ammonium salt, or C ₁ -C ₂₀ epoxy alkyl amide. 16. A polymer composition for the manufacture of a medicament for the removal of bile salts from a patient by ion exchange, comprising a therapeutically effective amount of the reaction product of: (a) one or more crosslinked polymers having repeating units of the formula:

Or its salt and its copolymer, wherein n is an integer; R ¹ is H or C ₁ -C ₈ alkyl; M is

or -ZR ² ; Z is O, NR ³ , S, or (CH ₂ ) _m ; m=0-10; R ³ is H or C ₁ -C ₈ alkyl; and R ² is

or

wherein P=0-10, and each of R ⁴ , R ⁵ or R ⁶ is H, C ₁ -C ₈ alkyl, or aryl; and (b) at least two alkylating agents, one of which has the formula RX, wherein R is _C1 - _C20 alkyl, X includes one or more electrophilic leaving groups, and the other An alkylating agent has the formula R'X, wherein R' is C ₁ -C ₂₀ alkyl ammonium, X includes one or more electrophilic electron leaving groups, provided that R ² includes R ⁴ , R ⁵ and At least one of R ³ , R ⁴ , R ⁵ and R ³ is H. 17. A polymer composition for use in the manufacture of a medicament for the removal of bile salts from a patient by ion exchange, comprising a therapeutically effective amount of the reaction product of: (a) one or more crosslinked polymers having repeating units of the formula:

Or its salt and its copolymer, wherein n is an integer; R ¹ is H or C ₁ -C ₈ alkyl; M is or -ZR ² ; Z is O, NR ³ , S, or (CH ₂ ) _m ; m=0-10; R ³ is H or C ₁ -C ₈ alkyl; and R ² is or wherein P=0-10, and each of R ⁴ , R ⁵ or R ⁶ is H, C ₁ -C ₈ alkyl, or aryl; and (b) at least two alkylating agents, one of which has the formula RX, wherein R is _C1 - _C20 alkyl, X includes one or more electrophilic leaving groups, and the other An alkylating agent has the formula R'X, wherein R' is C ₁ -C ₂₀ hydroxyalkyl, X includes one or more electrophilic leaving groups, with the proviso that ^R includes R ⁴ , R ⁵ and R ³ , at least one of R ⁴ , R ⁵ and R ³ is H. 18. A polymer composition for the manufacture of a medicament for the removal of bile salts from a patient by ion exchange, comprising a therapeutically effective amount of the reaction product of: (a) one or more crosslinked polymers having repeating units of the formula: Or its salt and its copolymer, wherein n is an integer; R ¹ is H or C ₁ -C ₈ alkyl; M is

or -ZR ² ; Z is O, NR ³ , S, or (CH ₂ ) _m ; m=0-10; R ³ is H or C ₁ -C ₈ alkyl; and R ² is

or

wherein P=0-10, and each of R ⁴ , R ⁵ or R ⁶ is H, C ₁ -C ₈ alkyl, or aryl; and (b) at least two alkylating agents, one of which is a C ₁ -C ₂₀ dihaloalkane and the other alkylating agent is a C ₁ -C ₂₀ alkylammonium salt, with the proviso that ^R Including R ⁴ , R ⁵ and R ³ , at least one of R ⁴ , R ⁵ and R ³ is H. 19. A polymer composition for the manufacture of a medicament for removing bile salts from a patient by ion exchange, comprising administering to the patient a therapeutically effective amount of one or more cross-linked polymers having repeating units of the formula

or its copolymer, wherein n is an integer, R ¹ is H or C ₁ -C ₈ alkyl; L is -NH- or G is or And each of R ² , R ³ and R ⁴ is independently H, C ₁ -C ₈ alkyl, or aryl. 20. The polymer composition of claim 19, wherein said polymer is crosslinked by a multifunctional crosslinking comonomer, said comonomer being about 1-25% by weight of the total monomers. 21. The polymer composition of claim 20, wherein the crosslinking comonomer is 2.5-20% by weight of the total monomers. 22. The polymer composition of claim 19, wherein the polymer further comprises one or more hydrophobic comonomers. 23. The polymer composition according to claim 22, wherein said hydrophobic comonomer comprises styrene and its fluorinated derivatives; ethyl vinylbenzene and its fluorinated derivatives; acrylamide and methyl N-Alkyl and N-aryl derivatives of acrylamide and their fluorinated derivatives; Alkyl and aryl esters of acrylic acid and their fluorinated derivatives; Alkyl and aryl esters of methacrylic acid and their fluorinated derivatives derivatives; 4-vinylbiphenyl and its fluorinated derivatives; 4-vinylanisole and its fluorinated derivatives; and 4-aminostyrene and its fluorinated derivatives. 24. The polymer composition of claim 19, wherein said polymer is characterized by repeating units of the formula

or a copolymer thereof, wherein n and G are as defined in claim 19. 25. The polymer composition of claim 19, wherein said polymer is characterized by repeating units of the formula

or a copolymer thereof, wherein n and G are as defined in claim 19. 26. The polymer composition of claim 19, wherein said polymer comprises repeating units of the formula

or its copolymer, wherein said n is as defined in claim 19. 27. The polymer composition of claim 19, further comprising styrene or a fluorinated derivative thereof as a comonomer. 28. The polymer composition of claim 19, wherein said polymer comprises repeating units of the formula

or its copolymer, wherein said n is as defined in claim 19. 29. A polymer composition for use in the manufacture of a medicament for the removal of bile salts from a patient by ion exchange, comprising a therapeutically effective amount of the reaction product of: (a) one or more crosslinked polymers having repeating units of the formula: Or its salt and its copolymer, wherein n is an integer; R ¹ is H or C ₁ -C ₈ alkyl; M is or -ZR ² ; Z is O, NR ³ , S, or (CH ₂ ) _m ; m=0-10; R ³ is H or C ₁ -C ₈ alkyl; and R ² is

or

wherein P=0-10, and each of R ⁴ , R ⁵ or R ⁶ is H, C ₁ -C ₈ alkyl, or aryl; and (b) at least one alkylating agent, one of which has the formula RX, wherein R comprises a _C4 - _C20 alkylammonium, and X comprises one or more electrophilic leaving groups, with the proviso is R ² includes R ⁴ , R ⁵ and R ³ , at least one of R ⁴ , R ⁵ and R ³ is H. Use of a polymer composition according to any one of claims 1-29 for the preparation of a medicament for removing bile salts from a patient.